PROJECT SUMMARY Adolescent smoking is a serious public health concern. Earlier initiation of smoking is a key factor in the development of nicotine dependence and associated mental health problems. Increasing evidence suggests that nicotine exposure during this critical period of development may have long-term cognitive consequences. Mouse models represent an important tool for identifying neural and genetic underpinnings of behavioral response to nicotine exposure across development, permitting experimental control over time course and genetic factors. The primary objective of this proposal is to identify sex and strain variability in long-term cognitive effects of adolescent nicotine exposure. We previously identified that adolescent C57BL/6J male mice exposed to nicotine display long-term cognitive deficits, as assessed by contextual fear conditioning, during adulthood. However, the effect of genetics (i.e. strain) and sex on these long-term consequences of adolescent nicotine exposure have not yet been investigated. Here, we aim to determine the interstrain variability in long-term cognitive effects of adolescent nicotine exposure in the founder strains of the Collaborative Cross (CC), a panel of recombinant inbred lines derived from eight genetically diverse inbred strains: five classical inbred strains (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ) and three wild-derived strains (CAST/EiJ, PWK/PhJ, WSB/EiJ). The CC panel represents far greater genetic diversity than previous recombinant inbred panels, and thus, represents an unprecedented opportunity for genetic analyses. Additionally, sex differences exist in smoking behaviors and the impact of smoking on cognition; therefore both male and female mice from each strain will be examined to identify sex effects and interactions with strain. Studies in this proposal will use the founders of the CC to characterize phenotypic differences across inbred strains (Aim 1) and to investigate sex differences within and across strains (Aim 2). The goal of this proposal is to demonstrate feasibility of using the CC panel for a forward genetics mapping study of the long-term detrimental effects of adolescent nicotine exposure. This proposal represents an important step in investigating an understudied area of the genetic underpinnings of the long-term consequences of adolescent nicotine exposure. Ultimately, investigating the genetic and neurobiological factors that underlie susceptibility to these long-term consequences may aid in the development of preventative treatments.